Project Summary The goal of this project is to advance a new treatment, TLY012, as the first, disease modifying agent that addresses two critical physiological and pathological features of chronic pancreatitis (CP) ? fibrosis and severe pain. CP is a progressive inflammatory disorder of the pancreas, predominantly caused by alcohol abuse. CP leads to pancreatic fibrosis and eventually irreversible destruction of the pancreas structure and function. Alcohol-related CP patients suffer from severe abdominal pain and increased risk of pancreatic cancer and diabetes. However, there are no therapeutic agents that either address CP progression or eliminate recurrent pain associated with CP, resulting in a significantly underserved patient population. TLY012 is a long-acting, PEGylated recombinant human TRAIL that selectively eradicates activated pancreatic stellate cells (aPaSC), the key mediators of CP that induce fibrosis and pain, while leaving normal cells unharmed. In our preclinical studies, we found that systemically administered TLY012 to alcohol-induced CP rat models simultaneously ameliorated pancreatic fibrosis and CP-associated pain as well as restored pancreatic function without causing any toxicity. The key objectives of the project involve the translation of TLY012 from the research stage to completion of an IND application to the FDA. In the first phase of the project (Phase I), manufacturing of TLY012 for pre-clinical development, will include optimization and scale-up of the existing manufacturing process to produce sufficient amount of TLY012 material. In addition, confirmatory pharmacology studies using the newly produced TLY012 in an alcohol-induced CP model and an initial toxicity assessment will be completed in rodents and non-human primates in order to enable further safety testing in GLP toxicology studies. The effects of alcohol on the pharmacokinetics (PK) of TLY012 in vivo will also be investigated. Assay development for PK and anti- drug antibodies (ADA) testing will be done to support sample analysis from PK, pharmacology and toxicity as well as formulation/stability studies. In the second phase of the project (Phase II), cGMP TLY012 will be produced using the final production methods for additional testing in GLP toxicity and future use in Phase 1 clinical studies. This will include technical transfer of the scaled process to qualified manufacturing site; with subsequent manufacturing of clinical material. Long term stability testing and clinical formulation development will also be initiated. Once TLY012 is produced, the final IND enabling GLP toxicology studies (sub-chronic and chronic) in rodents and non-human primates will be completed, a clinical protocol will be created. At appropriate stages of this project, requests will be filed for early advisory meetings with FDA to seek advice on adjustments to development strategy. As the final outcome of aforementioned studies an IND application will be filed to enable Phase 1 clinical studies in patients with alcohol-induced CP. Upon completion of project be successful, a highly innovative new drug, TL012 will be ready for entry into clinical trials.